The trk proteins are a family of receptor tyrosine kinases, whose function is the signal transduction of neurotrophins. The trk receptor family consists of three known members (A-C), each binding specific neurotrophins. Thus, the neurotrophins induce many of their effects through one of these trk receptors. Most germane to the current invention is the trkA receptor, which binds the neurotrophin Nerve Growth Factor (NGF).
NGF is an essential neurotrophin in maintaining homeostasis of nerve tissue in both the peripheral and central nervous system. The critical activity of NGF has been demonstrated in the development, maintenance, and repair of nerves. In addition to the homeostatic benefit of endogenous NGF, it has been suggested that exogenously administered NGF, molecules having NGF-agonist activity or molecules that can stimulate NGF or NGF-like activity, may be useful in treating damaged nerve tissue, e.g., nerve damage due to trauma, surgery, disease, old age, etc. It would be useful if an agent were available which would enhance the beneficial effects of endogenous or exogenous NGF, NGF-like activities or NGF agonists. Such an agent might be one which would increase the response of nerves to NGF via up-regulating the molecular target of NGF, i.e., its receptor, trkA. For further information, see: "Severe Sensory and Sympathetic Neuropathies in Mice Carrying a Disrupted trk/NGF Receptor Gene", Smeyne, R. J., et al., Nature, 368, pp. 246-248, Mar. 17, 1994.
Recently, it has been shown that the hormone estrogen regulates the gene coding the NGF receptor, viz., trkA. It has been known that estrogen appears to have a beneficial effect on maintaining healthy nerve tissue in many animal species, including humans. For further information, see: "Estrogen Differentially Regulates Estrogen and Nerve Growth Factor Receptor mRNAs in Adult Sensory Neurons", Sohrabji, F., et al., J. Neurosci., 14(2), pp.459-471 (1994) and "The Effects of Ovariectomy and Estrogen Replacement on trkA and Choline Acetyltransferase mRNA Expression in the Basal Forebrain of the Adult Female Sprague-Dawley Rat", McMillan, P. J., et al., J. Neurosci., 16(5), pp. 1860-1865, 1996 and references cited therein.
Therefore, it would seem reasonable that estrogens, e.g., 17-.beta.-estradiol, estrone, and the like, would be useful in the treatment of conditions where increasing the effect of molecules that directly or indirectly activate trkA receptor would be beneficial. However, estrogens are known to have many detrimental side-effects, e.g., cancer risk, uterine stimulation, and the like, vitiating their use in such cases.
It would be beneficial if an agent were available that would up-regulate the trkA/NGF system without estrogenic side-effects.